Interventions to Improve Medication Adherence Current Evidence and Future Directions Robby Nieuwlaat, PhD Tamara Navarro, MSc on behalf of the Patient Adherence Review team at the Health Information Research Unit
Presentation Outline 1. The importance of improving medication adherence 2. Cochrane systematic review update ‐ Methods Tamara Navarro 3. Cochrane systematic review update – Main results 4. Risk of bias in adherence intervention RCTs 5. Recommendations & Future directions
What is Medication Adherence? The extent to which a person's behaviour ‐ taking medication, following a diet, and/or executing lifestyle changes ‐ corresponds with agreed recommendations from a health care provider. ‐ World Health Organization, 2003
“Adherence to medications” is the process by which patients take their medications as prescribed, further divided into three quantifiable phases: “Initiation”, “Implementation” and “Discontinuation” ‐ The Ascertaining Barriers for Compliance project – Final Report 2012 (www.ABCproject.eu)
The Increasing Importance of Adherence Increasing number of self‐administered treatments Surging burden of chronic diseases Increasing shift from in‐patient care to community care Our ability to help patients adhering has not kept pace Thus, the gap between potential and actual patient health has widened
Good Adherence Saves Lives MORTALITY
GOOD ADHERENCE
POOR ADHERENCE
Simpson et al, BMJ, June 2006
Importance of Adherence in General
“healthy adherer effect”
Association between adherence to placebo and mortality
Simpson et al, BMJ, June 2006
Observational Example of Consequences De Vera MA, et al. Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review. 2014 Mortality
CVD outcomes
Adherence to Unsafe Therapy
Simpson et al, BMJ, June 2006
What Are Adherence Levels in Practice? TASK
Screening in community Referral from screening Staying in care Follow‐up appointments Medications Weight loss Smoking cessation
NON‐ ADHERENCE RATES*
35%‐90% 50%‐65% 31%‐66% 16%‐84% 31%‐58% 29%‐100% 71%‐96%
* Sackett and Snow, 1979
In individuals, adherence ranges from 0% to >100%
History of the PAR Review • 1996 Update – 13 studies (2 acute; 11 chronic)
• 2002 Update – 33 studies (3 acute; 30 chronic)
• 2005 Update – 57 studies (8 acute; 49 chronic)
• 2008 Update – 78 studies (9 acute; 69 chronic)
Why Update? Previous update (2008) • No clear evidence of effective interventions • Poor quality of trials Expected changes • 50 new RCTs (based on trend) • Innovative interventions & technologies • Improved study quality
Interventions to Improve Medication Adherence Cochrane Systematic Review Update
Nieuwlaat R, Wilczynski N, Navarro T, Hobson N, Jeffery R, Keepanasseril A, Agoritsas T, Mistry N, Iorio A, Jack S, Sivaramalingam B, Iserman E, Mustafa RA, Jedraszewski D, Cotoi C, Haynes RB
Primary Objective
To assess the effects of interventions intended to enhance patient adherence to prescribed medications for medical conditions, on both medication adherence and clinical outcomes.
Electronic System Web‐based database management system to facilitate screening, data extraction, adjudication of disagreements, author review and confirmation of data, production of data tables, and production of data files for future research:
Selection Criteria (1) Types of Studies •
RCTs with unconfounded tests of interventions
Types of Participants • •
Patients who are prescribed medications for medical (including psychiatric) disorders Excluded: studies targeting patients with addictions
Types of Interventions •
An intervention that serves to affect patients’ adherence to self-administered prescribed medication
Selection Criteria (2) Types of Outcome Measures • At least one adherence measure, AND • At least one clinical outcome, AND • Adequate follow-up: >80% follow-up in all treatment groups Long-term regimens with initial positive findings had to have at least a 6 month follow-up period
Search Methods • Studies from 2008 update were assessed for carry‐over • We updated searches on 11 January 2013: The Cochrane Library, including CENTRAL (via http://onlinelibrary.wiley.com/cochranelibrary/search/) MEDLINE, EMBASE, PsycINFO (all via Ovid) CINAHL (via EBSCO) Sociological Abstracts (via ProQuest)
• Bibliographies in articles on patient adherence, and contacted authors of relevant original and review articles → 1st and 2nd screening in duplicate; disagreements resolved by adjudicator
Data Extraction Methods • Data extracted in duplicate; disagreements resolved by adjudicator • Similar data as previous update, with addition of: • Cochrane Risk of Bias • Information on theoretical background and tailoring of interventions
Included Studies 5 studies from the 2008 update were excluded after detailed review 2 did not address self‐administered medications, 1 had 1 medication • 27 RCTs targeted 1 medication • 15 RCTs targeted unknown number of medications
Cautionary Tale ANY medical condition included, to: • Get a complete overview of the research field • Account for the fact that adherence problems are often comparable • Not exclude multi‐morbidity Large variety in: • Study settings • Clinical conditions • Recruitment methods • Treatment regimens • Intervention types • Adherence measures • Clinical outcome measures Insufficient common ground for quantifying differences between groups or estimating pooled effect sizes
Is Heterogeneity Inevitable? ANY medical condition included, to: • Get a complete overview of the research field • Account for the fact that adherence problems are often comparable • Not exclude multi‐morbidity Large variety in: • Study settings • Clinical conditions • Treatment regimens • Intervention types • Adherence measures • Clinical outcome measures ABC final report Only RCTs measuring adherence with MEMS: I2 = 98.88%
How to Analyze Heterogeneous Results?
Dr Joanne McKenzie
Risk of Bias Considering the large heterogeneity among RCTs, we chose to focus on RCTs with the lowest risk of bias, for: Random sequence generation Concealment of treatment allocation Blinding the assessment of the primary clinical outcome 17 RCTs had a low RoB; 7 from previous update, 10 new
• Cochrane ‘Risk of Bias’ tool (Higgins 2011) • Manuscript text (and author feedback) typically provided insufficient details to determine some RoB measures
RCTs with Lowest Risk of Bias 4 RCTs also had a low RoB for measuring adherence Gray 2012 Chung 2011 Solomon 2012 Haynes 1976
13 RCTs had high/unknown RoB for measuring adherence Ellis 2012 Wu 2006 Farooq 2011 Weber 2004 Morgado 2011 Laporte 2003 Lester 2010 Stevens 2002 Martins 2009 Nazareth 2001 Simoni 2009 Walley 2001 Simoni 2007
Example Low RoB – Gray 2012 Methods • Participants: 27 patients with new ocular hypertension or open‐angle glaucoma • Intervention: Delivered by a glaucoma trained nurse Assessment of patient needs, beliefs, and potential solutions Devise a 1 year individualized care plan Planning five face‐to‐face / phone follow‐up contacts for reassessment • Control: care as usual • Adherence measurement: pharmacist report (low RoB) • Clinical outcomes: intraocular pressure & care changes (routine medical charts) • Timelines: intervention during 12 months, no intervention at months 12‐24
Results • At 12 months: Intervention more patients with 100% refill, no differences clinical outcomes • At 24 months: Control had increased fluctuation of intraocular pressure and care changes • Differences at 24 months due to chance?
Example Low RoB – Solomon 2012 Methods • Participants: 2097 low‐income older adults who were initiating osteoporosis medication • Intervention: 7 informational mailings addressing osteoporosis 8 phone counseling sessions by health educators using motivational interviewing • Control: only 7 informational mailings addressing osteoporosis • Adherence measure: medication possession ratio, using pharmacy claims data (low RoB) • Clinical outcomes: self‐reported fractures or falls • Timelines: 1 year follow‐up
Results • No difference in adherence and clinical outcomes • 113‐day time lag between identifying eligible patients and making the first phone call
Lowest RoB Studies ‐ Description • Interventions were generally complex, trying to overcome multiple barriers to adherence • Primarily involved enhanced support from family, peers, or allied health professionals • Of these 17 RCTs: 5 improved both adherence and clinical outcomes 3 improved only adherence outcomes 1 improved only clinical outcome 8 did not improve adherence or clinical outcomes • This was a similar success rate to that found in the 21 newly included studies in the 2008 update (Haynes 2008)
Required Advances
Why We Need Advances • Lack of convincing evidence for consistent, reliable, and potentially practical and cost‐effective interventions • Only modest reduction of Risk of Bias in the 35 year publication timespan in the cumulative review Pearson correlation 0.156, 2‐tailed p=0.035 • Despite a growth in the number of adherence RCTs and a slight improvement in study methodology, largely the same methodological drawbacks endure • The adherence research field is slow to catch up with the increasing availability of self‐administered medications and technological innovations
Selecting Patients Who Need Help Zwikker H, et al. Psychosocial predictors of non‐adherence to chronic medication: systematic review of longitudinal studies. 2012
Kardas P, et al. Determinants of patient adherence. 2013 (SR of reviews) • Multiple determinants, many inconsistencies
Low adherence is very hard to predict
Patient Recruitment ‐ Adherence Of the 109 new RCTs • Only 11 (10%) enrolled patients based on their baseline adherence • 52 did not consider adherence status for enrollment • 46 studies did not provide sufficient details to determine whether they considered adherence status for enrollment • Of 56 RCTs (51%) measuring baseline adherence, only 11 reported results based on baseline adherence status • Baseline adherence measurement possible? 71 (65%) targeted patients who were already on the medication 38 (35%) targeted newly starting patients (proxy: adherence to other med, prior visit attendance?) ‘Run‐in’ period before randomization to identify NON‐adherent participants?
Patient Recruitment ‐ Quality
Measuring Adherence In the 109 new RCTs • Overall 163 measures of adherence were included • The median overall quality of these measures was 4 on a scale from 0 to 9 (next slide) • 14 studies (13%) used a measure of adherence that was valid, reliable, objective, unobtrusive and longitudinal • 52 studies (48%) used only subjective adherence measures Major issues • Validation • Assessing reliability • Optimizing objectivity • Blinding • Longitudinal measures vs ‘snapshots’
Measuring Adherence ‐ Quality
Adherence Measures in SR ‐ Quality
Why Require Clinical Outcomes? • Adherence measurement typically has a high risk of bias (clinical events; important to patients and objectively verifiable) • Potential adverse effects despite improved adherence: Loss of privacy / autonomy Increased adverse effects of medication Attention drawn away from other health issues • Short‐term improvements in adherence are not important for chronic care if they cannot be sustained Of 109 new RCTs • Reporting patient‐important clinical events ‐ 34 (31%) • Reporting biological outcomes ‐ 73 (67%) • Reporting patient reported outcomes ‐ 71 (65%)
Study Design Among 109 new RCTs • Concealment of allocation prior to the exact time of randomization was unclear in 71 trials (65%) and not done in 3 (3%) • ‘Active’ control group (balance the increased attention) – 27 (25%) • Blinding Of patients ‐ 9 (8%) Of personnel ‐ 7 (6%) Neither are fatal flaws, IF adherence measures are objective and outcome assessors can be blinded • Using a cluster design ‐ 11 (10%)
Study Power Minimum sample size requirement As a general guide, studies with a single intervention group and control group would need to include at least 60 participants per group if they are to have at least 80% power to detect an absolute difference of 25% in the proportion of patients judged to have adequate adherence Actual power of RCTs • According to this rule, the new RCTs were as likely to be underpowered (44/109; 40%) as RCTs in the previous update (36/78; 46%) • Among the 17 lowest risk of bias RCTs in the present update, 4 had insufficient power
Intervention Design • Intervention design explicitly based on theoretical framework – 39% • Key stakeholders involved in intervention design – 33% • ‘Kitchen sink’ approaches could work. If effective: Test individual components Assess cost‐effectiveness Assess practicality
Intervention Types • Allied health professionals, lay health workers – Specific roles & standardized training • Technology: mobile devices, web‐based, new developments • Enhanced social support – peers, family, friends • Combination therapy, simplified dosing • Interventions obviating the need for adherence (implantable) • Novel ideas!!
Incomplete Reporting
Hoffmann TC, et al. Better reporting of interventions: template for intervention description and replication (TIDieR) checklist and guide. 2014
Review Limitations & Remedies Limitations • Missed studies • Eligibility criteria • Risk of bias assessment Remedies • Report missed studies • Provide suggestions for classification of RCTs • Also assess systematic reviews on specific conditions • Share data
Implications for Practice New studies and high quality studies frequently used interventions that are complex, and delivered (partly) by allied health care professionals with regular patient interaction HOWEVER 1. Even these complex, intensive long‐term strategies were not very effective, despite the effort and resources they can consume 2. There is insufficient evidence at present to conclude that newer interventions (SMS, web‐based) can assist in improving adherence 3. There is no evidence that low adherence can be ’cured’ Recommendation (for now) Adherence approaches should be maintained for as long as the treatment is needed, aiming for cost‐effective* integration into the care system * Oberje EJ, et al. Cost Effectiveness of Medication Adherence‐Enhancing Interventions: A Systematic Review of Trial‐ Based Economic Evaluations. 2013
Implications for Research 1. Barriers causing low medication adherence need to be better understood 2. Theoretical frameworks to aid in the design of complex interventions • Provide rationale of design and hypothesized mechanisms of effect • If effective, evaluate components in factorial design
3. Adherence research methodology needs improvement in several areas: • • • •
Recruitment of patients with low adherence Employ best‐in‐class adherence measurements (blinding) Power studies to find potentially meaningful effects Provide sufficient details on research methods in publications
4. Intervention types to consider • Treatments that obviate the need for adherence (e.g. implantable) • Simplified regimen • Newer information‐communication technologies
Data Sharing • Low adherence is a ubiquitous problem for all self‐administered medications • Joined efforts are needed to advance the field HIRU makes its database available for collaborations on sub‐analyses Current sub‐analyses • Risk of bias • Technology‐mediated interventions • HIV/AIDS • Pediatric interventions • Use if theory to design interventions
Cochrane Publication Nieuwlaat R, Wilczynski N, Navarro T, Hobson N, Jeffery R, Keepanasseril A, Agoritsas T, Mistry N, Iorio A, Jack S, Sivaramalingam B, Iserman E, Mustafa RA, Jedraszewski D, Cotoi C, Haynes RB. Interventions for enhancing medication adherence. Cochrane Database of Systematic Reviews 2014, Issue 11. Art. No.: CD000011. DOI: 10.1002/14651858.CD000011.pub3
Publication date:
November 20th, 2014